Design: The investigators conducted a systematic review and meta-analysis of all available randomized trials evaluating the use of bisphosphonates in cancer patients with metastatic bone disease. Patients with multiple myeloma were included, but those with other hematological cancers were not. The investigators identified potentially relevant trials by searching electronic databases (MEDLINE, CancerLit, EMBASE, Science Citation Index, Cochrane Database), manually searching 3 oncology journals and abstracts from international meetings, scanning reference lists of articles, and consulting experts in the specialty and drug companies for unpublished data. All foreign-language articles were translated in full into English. The reporting of concealment and blinding in each trial was graded by the authors. Data were pooled when appropriate using a random effects model and weighted according to the inverse of their variance. No sensitivity analyses were defined a priori.

Commentary: In the hierarchy of research design, the results of a meta-analysis of high-quality, homogeneous, randomized controlled trials represents the highest level of evidence to guide patient care.1,2,3 Ross and coauthors should be commended for their rigorous systematic review and meta-analysis. The validity of the results from this review are strengthened by the inclusion of randomized controlled trials, a comprehensive search strategy, the inclusion of unpublished reports and non-English-language trials, and homogeneity of results across studies.1,2,3 The authors did not report whether searches, assessment of study validity or data abstraction were performed in duplicate. The reproducibility of the methodology (i.e., inter-reviewer agreement statistics) would improve confidence in the validity of the review.

Practice implications: Bisphosphonates are effective in decreasing skeletal morbidity. Although morbidity is decreased and time to first skeletal event is increased, overall survival is not increased. Bisphosphonate therapy should be initiated when skeletal metastases are identified and continued for at least 6 months for clinical benefit. Although no direct comparison between intravenous and oral routes of administration were available, indirect comparisons favour the intravenous route.